The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Lower Urinary Tract Symptoms (LUTS)
Typical clinical symptoms included in this group are hesitance, poor urinary stream, terminal drippling and incomplete bladder emptying. The main functional cause of LUTS is urethral sphincter dysfunction. The urethral sphincter consists of a voluntary (striated) sphincter (rhabdosphincter) and an involuntary (smooth) sphincter. The distal part of the male rhabdosphincter surrounds the membranous part of the urethra and is called external sphincter. The upper or prostatic part of the rhabdosphincter is layered out over the anterior and lateral aspects of the prostate and embedded in the prostatic stroma in men. The urethral smooth muscle is located at the bladder neck and prostatic urethra in men. Lowering of resistance of the smooth and striated sphincter, associated with coordinated detrusor contraction determines complete micturition. In urethral sphincter dysfunction an increased intraluminal bladder pressure is needed to empty the bladder. In the initial stages, there is no reduction in the flow rate because the maximum micturition pressure compensates for the increased outflow resistance. The reduction of the flow rate developing in more advanced clinical stages of urethral dysfunction correlates poorly with the degree of prostatic enlargement.
Three different clinical outcomes have been described: 1) bladder neck dyssynergia, 2) external sphincter pseudodyssynergia and 3) Hinman syndrome. They have all been defined as detrusor urethral sphincter dyssynergia.
Bladder neck dyssynergia is defined as the inability of the bladder neck to open properly and assume a funnel shape in the presence of a normal detrusor contraction. Video imaging techniques allow the diagnosis of the smooth sphincter dyssynergia. The bladder neck dyssynergia is a life-long condition, and virtually never occurs in the female. The cause of the bladder neck dyssynergia is unknown.
During the normal micturition cycle, an increase in external sphincter electromyographic activity accompanies bladder filling (continence reflex). This is followed by relaxation of rhabdosphincter and the pelvic floor muscles, which begins before or at the beginning of the detrusor contraction and persists throughout the contraction. Rhabdosphincter dyssynergia is defined as an inappropriate increase in striated urethral muscle (external urethral sphincter) activity during a detrusor contraction and is a well recognized cause of voiding dysfunction in patients with upper neurone lesions. This overcompensation owing to the loss of supraspinal influences is done to counteract the elevated bladder pressure caused by uninhibited detrusor contraction (an exaggerated continence reflex). In external sphincter pseudodyssynergia, incoordination between the bladder and urethral sphincter is not due to a neurological lesion but is secondary to a dysfunction resulting in an increased tone of the external sphincter and the pelvic floor muscles. Pseudodyssynergia is determined by intermittent increase in sphincter EMG and/or intermittent narrowing of the urethra at this site.
Urodynamic investigations in children with an abnormal voiding pattern have shown dyssynergia between the detrusor and striated urethral sphincter in the absence of neurological disease (non-neurogenic neurogenic bladder or the Hinman syndrome). This appears to result from unintentional, habitual contractions of the striated urethral sphincter in response to involuntary bladder contraction to prevent urinary incontinence. This dyssynergia probably may at least partly represent a learned habit. The relationship between the Hinman syndrome and the external sphincter pseudodyssynergia is not known.
Patients with urethral sphincter dysfunction may develop secondary detrusor instability with irritative symptoms of frequency, urgency and nocturia.
LUTS may be associated with chronic pelvic pain. The article written by Oliver W Hakenberg and Manfred P Wirth (Urol Int 2002:68:138-143), concerns chronic pelvic pain syndrome (CPPS) in men. This is defined as a condition of pelvic pain of more than 6 months duration. Certain conditions causing CPPS are mentioned, namely abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndrome, trigonitis and orchialgia. Interstitial cystitis in men or women will also typically result in pelvic pain. A primary difficulty noted in patients with CPPS is the inability to voluntarily relax the external sphincter and the pelvic floor muscles. This will result in the emergency of LUTS and dyssynergic voiding.
On the basis of the findings in experimental animals (Streng: Hormone-related reversible urinary rhabdosphincter disorder in male laboratory rodents—possible clinical implications. Academic dissertation, University of Turku, 2002), we suggest that the increased ratio of estrogen to androgen concentration (relative overaromatization of androgens) in the organism plays a role in the development of the urethral sphincter dysfunction in men. In male animals chronically treated with estrogen bladder outlet obstruction develops with complete urinary retention and hypertrophy of the bladder wall. Neonatally estrogenized animals have a lower voided urine volume and decreased ratio of urinary flow rate-to-bladder pressure, which are consistent with infravesical obstruction. These urodynamic changes of the neonatally estrogenized animals are reversed after the treatment of aromatase inhibitor in adulthood. The urethral smooth and striated sphincters and neurones innervating them show androgen and estrogen receptors suggesting that they are the potential target of androgens and estrogen actions. The prostate of these animals have reduced size and show signs of inflammation.
U.S. Pat. No. 5,972,921 describes a method for the treatment of detrusor urethral sphincter dyssynergia in men by administering an aromatase inhibitor to the patient. Said patent gives a summary of the clinical symptoms of male functional detrusor urethral sphincter dyssynergia and its treatments taking into account especially the possible hormonal background of the symptoms. Aromatase inhibitors, when studied in men with urinary symptoms (A Radlmaicr et al., The Prostate 29:199-208 (1996); J C Gingell et al., The Journal of Urology, vol. 154, 399-401, August 1995), increase the concentrations of testosterone. This causes an increase in the size of prostate and on the other hand may worsen the static obstruction caused by the enlarged prostate and consequently the symptoms. Therefore, other mechanisms of action are desirable. SERMs, which act as antiestrogens in the urinary tract, decrease the detrimental effect of natural estrogens without stimulating the prostate size. They can be considered as potentially beneficial compounds in treating the symptoms and functional causes of LUTS.
Selective Estrogen Receptor Modulators
“SERMs” (selective estrogen receptor modulators) have both estrogen-like and antiestrogenic properties (Kauffman & Bryant, Drug News Perspect 8:531-539, 1995). The effects may be tissue-specific as in the case of tamoxifen and toremifene which have estrogen-like effects in the bone, partial estrogen-like effect in the uterus and liver, and pure antiestrogenic effect in breast cancer. Raloxifene and droloxifen are similar to tamoxifen and toremifene, except that their antiestrogenic properties dominate. They are known to decrease total and LDL cholesterol, thus diminishing the risk of cardiovascular diseases, and they may prevent osteoporosis and inhibit breast cancer growth in postmenopausal women. There are also almost pure antiestrogens under development. They are mainly aimed at the treatment of breast cancer (Wakeling & Bowler, J Steroid Biochem 30:1-6, 1988).
A review of investigated and/or marketed SERM compounds is published in V Craig Jordan, J Medicinal Chemistry (2003):46, No. 7.